The hypothesis for the competitive renewal of the grant, Translational Multimodality "Antibody" Therapy, is that the therapeutic index for radioisotopic molecular targeted radiotherapy (RMTR) can be dramatically improved using novel small molecules and delivery strategies. RMTR has expanded the usefulness of radiation to treat widespread cancer, and small radioisotope carrier molecules can achieve therapeutic indices 10-100X better than that currently achieved using macromolecular MAb carriers. This program has renewed its emphasis on translational research to apply novel science and resources for the development of drugs and strategies to be evaluated in preclinical studies (before transfer to patients). Although the proposals are potentially applicable to most cancers, the focus will be on lymphomas and prostate cancer because of the need for novel treatment and substantial progress achieved using conventional radioimmunotherapy. Using insights from our experience with Lym-1-MAb and HLA-DR targeting, and a combination of unusual capabilities, we have generated synthetic, high affinity (linked) ligands (SHALs) in the first project that selectively bind to unique sites on the beta subunit of HLA-DR, a protein shown to be relatively specific for the malignant lymphocytes of B-lymphomas and leukemias. These novel molecules have been shown to bind selectively to HLA-DR10 and human lymphoma cells and will be used as radioisotopic carriers for systemic radiotherapy. In the second project, novel bispecific, multivalent single-chain MAbs, against the tandem repeat of the mucin protein characteristic of adenocarcinomas and against the DOTA chelator for radiometals, have been generated and placed on a PEGylated scaffold for use in a pretargeting RIT strategy for prostate cancer. Multivalent DOTA will be used as the radiometal carrier. PEGylated bivalent scFvs that bind selectively to prostate cancer have been synthesized. In the third project, the inventor of the "one bead, one peptide" combinatorial libraries has generated serine protease (Activase(R), TNKase(R) biodegradable linkers, stable in plasma, to reduce radiation doses to all normal tissues by eliminating radioisotope carriers from the blood "on demand". In the past, we showed that cathepsin-degradable peptides in radiometal-labeled MAbs reduced hepatic radiation dose. The proposed strategy decreases radiation dose to all normal tissues and is applicable to other radioisotopic targeting systems, both in development and approved, and as a clearance vehicle for pregargeting strategies. Four cores support the projects. Dramatic progress has been made and the likelihood of success is certain.